Daulatzai Mak Adam
Sleep Disorders Group, EEE/Melbourne School of Engineering, The University of Melbourne Parkville, Victoria 3010, Australia.
Am J Neurodegener Dis. 2016 Jun 1;5(2):102-30. eCollection 2016.
Alzheimer's disease (AD) is a chronic progressive neurodegenerative condition of the brain, and it is the most common cause of dementia. Several neurobiological etiologies of AD are described in the literature. These include vascular, infectious, toxic, nutritional, metabolic, and inflammatory. However, these heterogeneous etiologies have a common denominator - viz. Inflammation and oxidative stress. Lipopolysaccharide (LPS) elevates the synthesis of proinflammatory cytokines and chemokines; chronically, together they trigger various pathological responses in the periphery and the CNS including dysfunctional memory consolidation and memory decline. Aging - the main risk factor for AD is inherently associated with inflammation. There are several age-related comorbidities that are also associated with inflammation and oxidative stress. Such co-prevailing aggravating factors, therefore, persist against a background of underlying aging-related pathology. They may converge, and their synergistic propagation may modify the disease course. A critical balance exists between homeostasis/repair and inflammatory factors; chronic, unrelenting inflammatory milieu succeeds in promoting a neuroinflammatory and neurodegenerative outcome. Extensive evidence is available that CNS inflammation is associated with neurodegeneration. LPS, proinflammatory cytokines, several mediators secreted by microglia, and oxidative-nitrosative stress in concert play a pivotal role in triggering neuroinflammatory processes and neurodegeneration. The persistent uncontrolled activity of the above factors can potentiate cognitive decline in tandem enhancing vulnerability to AD. Despite significant progress during the past twenty years, the prevention and treatment of AD have been tantalizingly elusive. Current studies strongly suggest that amelioration/prevention of the deleterious effects of inflammation may prove beneficial in preventing AD onset and retarding cognitive dysfunction in aging and AD. A concerted multi-focal therapeutic effort around the inflammation-oxidative-nitrosative stress paradigm may be crucial in preventing and treating AD. This paper informs on such relevant polypharmacy approach.
阿尔茨海默病（AD）是一种慢性进行性脑部神经退行性疾病，也是痴呆最常见的病因。文献中描述了AD的几种神经生物学病因。这些病因包括血管性、感染性、中毒性、营养性、代谢性和炎症性。然而，这些不同的病因有一个共同的因素，即炎症和氧化应激。脂多糖（LPS）可提高促炎细胞因子和趋化因子的合成；长期来看，它们共同引发外周和中枢神经系统的各种病理反应，包括记忆巩固功能障碍和记忆衰退。衰老——AD的主要危险因素，本质上与炎症相关。还有几种与年龄相关的合并症也与炎症和氧化应激有关。因此，这些共同存在的加重因素在潜在的衰老相关病理背景下持续存在。它们可能会汇聚，其协同作用可能会改变疾病进程。体内平衡/修复与炎症因子之间存在关键平衡；慢性、持续的炎症环境成功地促进了神经炎症和神经退行性变的结果。有大量证据表明中枢神经系统炎症与神经退行性变有关。LPS、促炎细胞因子、小胶质细胞分泌的几种介质以及氧化-亚硝化应激共同在触发神经炎症过程和神经退行性变中起关键作用。上述因素持续不受控制的活动可增强对AD的易感性，同时加剧认知衰退。尽管在过去二十年中取得了重大进展，但AD的预防和治疗仍然难以捉摸。目前的研究强烈表明，改善/预防炎症的有害影响可能对预防AD发病和延缓衰老及AD患者的认知功能障碍有益。围绕炎症-氧化-亚硝化应激范式进行协调一致的多靶点治疗努力可能对预防和治疗AD至关重要。本文介绍了这种相关的联合用药方法。
